early stage nsclc: imprimatur of adjuvant therapy corey j langer md, facp professor of medicine...

Early Stage NSCLC: Imprimatur Early Stage NSCLC: Imprimatur of Adjuvant Therapyof Adjuvant Therapy

Corey J Langer MD, FACPCorey J Langer MD, FACPProfessor of MedicineProfessor of Medicine

Director of Thoracic OncologyDirector of Thoracic OncologyAbramson Cancer CenterAbramson Cancer Center

University of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PA 19104Philadelphia, PA 19104

Overview of Recent Data

Disclosures: Past 10 yrsDisclosures: Past 10 yrs• Grant/Research Support:Grant/Research Support:

– Bristol Myers SquibbBristol Myers Squibb, Pfizer, , Pfizer, Imclone, LillyImclone, Lilly, Schering-Plough , Schering-Plough Research Institute, Research Institute, Sanofi-AventisSanofi-Aventis, Amgen, Cell Therapeutics, , Amgen, Cell Therapeutics, OrthoBiotech, Celgene, Vertex, OrthoBiotech, Celgene, Vertex, Genentech, OSIGenentech, OSI, , AstraZeneca, Pfizer, Medimmune, GSKAstraZeneca, Pfizer, Medimmune, GSK

• Scientific Advisor:Scientific Advisor:– Bristol Myers Squibb, Imclone, Sanofi-AventisBristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer, , Pfizer,

GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Genentech, OSI, Savient, Bayer/Onyx, Abraxis, Clarient, Savient, Bayer/Onyx, Abraxis, Clarient, Morphotek, Biodesix, AVEO, SyntaMorphotek, Biodesix, AVEO, Synta

• Speakers Bureau:Speakers Bureau: curtailed as of 12/10curtailed as of 12/10– Bristol Myers Squibb, Imclone, Sanofi-Aventis, Lilly, Genentech, Bristol Myers Squibb, Imclone, Sanofi-Aventis, Lilly, Genentech,

OSIOSI

3

Welcome to Winter in NJ 2-14

Stage is Destiny!Stage is Destiny!

UICC6 T/M Descriptor Proposed T/M N0 N1 N2 N3

T1 (< 2 cm) T1a IA IIA IIIA IIIB

T1 (> 2-3 cm) T1b IA IIA IIIA IIIB

T2 ( 3 to < 5 cm) T2a IB IIA IIIA IIIB

T2 (>5-7) T2b IIA IIB IIIA IIIB

T2 (> 7 cm) T3 IIB IIIA IIIA IIIB

T3 invasion T3 IIB IIIA IIIA IIIB

T4 (same lobe nodules) T3 IIB IIIA IIIA IIIB

T4 (extension) T4 IIIA IIIA IIIB IIIB

M1 (ipsilateral Lung) T4 IIIA IIIA IIIB IIIB

T4 (pleural effusion) M1a IV IV IV IV

M1 (contralateral lung) M1a IV IV IV IV

M1 (distant) M1b IV IV IV IV

New Staging System (IASLC ’07)New Staging System (IASLC ’07)to be instituted 2009to be instituted 2009

UICC6 T/M Descriptor Proposed T/M N0 N1 N2 N3

T1 (< 2 cm) T1a IA IIA IIIA IIIB

T1 (> 2-3 cm) T1b IA IIA IIIA IIIB

T2 ( 3 to < 5 cm) T2a IB IIA IIIA IIIB

T2 (>5-7) T2b IIA IIB IIIA IIIB

T2 (> 7 cm) T3 IIB IIIA IIIA IIIB

T3 invasion T3 IIB IIIA IIIA IIIB

T4 (same lobe nodules) T3 IIB IIIA IIIA IIIB

T4 (extension) T4 IIIA IIIA IIIB IIIB

M1 (ipsilateral Lung) T4 IIIA IIIA IIIB IIIB

T4 (pleural effusion) M1a IV IV IV IV

M1 (contralateral lung) M1a IV IV IV IV

M1 (distant) M1b IV IV IV IV

New Staging System (IASLC ’07) New Staging System (IASLC ’07) Instituted 2009Instituted 2009

Limitations of Earlier Adjuvant Limitations of Earlier Adjuvant TrialsTrials

• Use of regimens with marginal activity in Use of regimens with marginal activity in advanced NSCLCadvanced NSCLC

• Inclusion of patients with compromised Inclusion of patients with compromised PS and multiple co-morbiditiesPS and multiple co-morbidities

• Difficulty administering systemic therapy Difficulty administering systemic therapy in the post-op settingin the post-op setting

• Inadequate power or overly ambitious Inadequate power or overly ambitious survival endpointssurvival endpoints

Surgery plus Chemotherapy Surgery

0

20

40

60

80

100

Perc

en

tag

e

Su

rviv

al

Time from Randomization (months)

12

18

24

36

48

54

60

0

BMJ 31: 899-908, 1995

1995 Meta-AnalysisAdjuvant Cisplatin Trials n=1394

HR 0.87p=0.08

5% absolute survival benefit at 5 years, NS

Plaitnum-Based Adjuvant Trials in Plaitnum-Based Adjuvant Trials in Resected NSCLCResected NSCLC

Plaitnum-Based Adjuvant Trials in Plaitnum-Based Adjuvant Trials in Resected NSCLCResected NSCLC

Trial N. of Patients HR (95%CI)BMJ meta 1394 0.87 (0.74-1.02)IALT 1867 0.86 (0.76-0.98)ALPI 1209 0.96 (0.81-1.13)E3590 488 0.93 (0.74-1.18)BLT 381 1.02 (0.77-1.35)BR-10 482 0.70 (0.53-0.92)CALGB9633 344 0.63 (0.60-1.07) ANITA 840 0.79 (0.66-0.95)LACE meta 4584 0.89 (0.82-0.96)

NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06

Plaitnum-Based Adjuvant Trials in Plaitnum-Based Adjuvant Trials in Resected NSCLC: Longterm ResultsResected NSCLC: Longterm Results

Plaitnum-Based Adjuvant Trials in Plaitnum-Based Adjuvant Trials in Resected NSCLC: Longterm ResultsResected NSCLC: Longterm Results

Trial N. of Patients HR (95%CI)BMJ meta 1394 0.87 (0.74-1.02)IALT 1867 0.91 (0.81-1.02)ALPI 1209 0.96 (0.81-1.13)E3590 488 0.93 (0.74-1.18)BLT 381 1.02 (0.77-1.35)BR-10 482 0.70 (0.53-0.92)CALGB9633 344 0.80 (0.60-1.07) ANITA 840 0.79 (0.66-0.95)LACE meta 4584 0.89 (0.82-0.96)

NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06

Intl Adjuvant Lung Cancer Trial Intl Adjuvant Lung Cancer Trial (IALT) 1867 pts, I-III(IALT) 1867 pts, I-III

• Randomized to obs vs. 4 cycles post-op chemo*Randomized to obs vs. 4 cycles post-op chemo*• Radiation therapy optional (~30%)Radiation therapy optional (~30%)• 4.1% absolute benefit at 5 years, p<0.034.1% absolute benefit at 5 years, p<0.03††

– Stage III > Stage I benefit Stage III > Stage I benefit

• Diminished at 7 yr follow-upDiminished at 7 yr follow-up• HR 0.86 [0.76-0.98] HR 0.86 [0.76-0.98] 0.91 [0.81-1.02]; 0.91 [0.81-1.02];

– p = 0.04 p = 0.04 0.1 after 5 yrs due to non-cancer deaths ^ 0.1 after 5 yrs due to non-cancer deaths ^

†Arriagado, NEJM 350:351, 2004, ^ Le Chevalier ASCO 2008

*cisplatin + etoposide or vinca alkaloid

Randomized International Adjuvant Lung Randomized International Adjuvant Lung Cancer Trial (IALT): Cisplatin-Based Cancer Trial (IALT): Cisplatin-Based

Chemotherapy vs No Chemotherapy for Chemotherapy vs No Chemotherapy for Resected NSCLCResected NSCLC

Stage I-III NSCLCComplete surgical resection within 60 days N=1867

Arm A*Cisplatin 80 mg/m2 4 cycles ORCisplatin 100 mg/m2 3-4 cycles ORCisplatin 120 mg/m2 3 cyclesPLUSEtoposide 100 mg/m2 3 days/cycle ORVinorelbine 30 mg/m2 weekly ORVinblastine 4 mg/m2 weekly OR Vindesine 3 mg/m2 weeklyn=935

Arm BObservation± thoracic radiotherapy 60 Gy†

n=932

*Each center selected which chemotherapy it would use. †Optional, but predefined by N stage at each center.Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation;

Arriagada et al. N Engl J Med. 2004;350:351.

RANDOMIZE

Adjuvant ChemotherapyAdjuvant Chemotherapy IALT n=1867IALT n=1867

• cDDP was 80 q 3 weeks X 4cDDP was 80 q 3 weeks X 4

100 q 4 weeks X 3-4100 q 4 weeks X 3-4

120 q 4 weeks X 3120 q 4 weeks X 3• 56% + Etoposide 10056% + Etoposide 100• 27% + Vinorelbine 3027% + Vinorelbine 30• 11% + Vinblastine 411% + Vinblastine 4• 6% + Vindesine 36% + Vindesine 3

Le Chevalier, ASCO 2003 abstract 6, NEJM 2004

Adjuvant ChemotherapyAdjuvant Chemotherapy IALT (International Adjuvant Lung Trial) n=1867IALT (International Adjuvant Lung Trial) n=1867

1995-20001995-2000

• 33 countries, initial accrual goal was 330033 countries, initial accrual goal was 3300

• 80/20 M/F80/20 M/F

• Mean age 59 (all Mean age 59 (all << 75) 75)

• Squamous 47%, ACAs 40%Squamous 47%, ACAs 40%

• Chemo to start Chemo to start << 60 days after surgery 60 days after surgery

• Median f/u: 56 monthsMedian f/u: 56 months

Le Chevalier, ASCO 2003 abstract 6, NEJM 1/04

Observation ± RT

Chemotherapy

Months

Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation. NEJM 1/04

IALT: Cisplatin-Based Chemotherapy vs IALT: Cisplatin-Based Chemotherapy vs No Chemotherapy for Resected NSCLC:No Chemotherapy for Resected NSCLC:

Overall Survival (Med F/U 56 mos)Overall Survival (Med F/U 56 mos)

0

20

40

60

80

100

0 12 24 36 48 60

HR=0.86 (0.76-0.98)

P<0.03

% S

urv

ival

IALT TrialIALT TrialARM Adjuvant chemo Control

Number of enrollees 935 932

Dead of disease progression 361 405

Tx-related deaths (n) 14 2

Compliance with RT (%) 71 85

Median DFS (mo) 39.4 34.3

2-yr DFS (%) 61 55

5-yr DFS (%) 39 34

Median Survival Time (mo) 50.8 44.4

2-yr OS (%) 70 67

5-yr OS (%) 44.5 40.4

• Benefit seen across all demographic variablesBenefit seen across all demographic variables– GenderGender– type of surgerytype of surgery– use of RTuse of RT– geographical locationgeographical location

• Greatest benefit in stage III pts (~7.5%)Greatest benefit in stage III pts (~7.5%)• In subgroup analyses, survival advantage for In subgroup analyses, survival advantage for

stage I and II was not statistically significantstage I and II was not statistically significantAdjAdj Control Control

Rel %↑Rel %↑– Stage IStage I 65.665.6 64.964.9 0.70.7– Stage IIStage II 46.546.5 43.243.2 3.33.3– Stage IIIStage III 37.437.4 29.929.9 7.57.5

IALT: Cisplatin-Based Chemotherapy vs IALT: Cisplatin-Based Chemotherapy vs No Chemotherapy for Resected NSCLC:No Chemotherapy for Resected NSCLC:

Overall SurvivalOverall Survival

935 775 619 520 447 372 282 208 125

932 780 650 550 487 399 300 208 133

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 years

chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years

control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years

HR: 0.91 (0.81-1.02, P = 0.10)

Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.

IALT: Cisplatin + a Vinca or Etoposide2008 Update: 7.5-Year Median Follow-Up

Criticisms of IALTCriticisms of IALT• Heterogenous staging, chemo and application of RT (HR favored Heterogenous staging, chemo and application of RT (HR favored

stage III, not stage I or II)stage III, not stage I or II)• Study actually closed earlier than planned because of emerging Study actually closed earlier than planned because of emerging

interest in neoadjuvant Txinterest in neoadjuvant Tx• Potential Molecular Imbalances: Results of ERCC1 suggest that Potential Molecular Imbalances: Results of ERCC1 suggest that

one can select a group more likely to benefit; other bio-correlatives one can select a group more likely to benefit; other bio-correlatives still pending still pending

• Elderly (> 75) excluded; how do we address this expanding cohort?Elderly (> 75) excluded; how do we address this expanding cohort?• Dissipation of survival benefit after 5 yearsDissipation of survival benefit after 5 years• Why was this trial positive when so many similar trials proved Why was this trial positive when so many similar trials proved

negative?negative?

Recent (-) Trials of AdjuvantRecent (-) Trials of AdjuvantCT in Completely Resected NSCLCCT in Completely Resected NSCLC

Study Country CT Regimen

# of Patient

s

Outcome

on OS

INT 0115

ALPI/EORTC

BLT

USA

Italy/Europe

International

VP16-P x 4

MVP x 3

V-P x 4

462

1197

481

Negative

Negative

Negative

2004: Paradigm Shift

Recently Completed (+) Randomized Recently Completed (+) Randomized Adjuvant Trials in Early Stage NSCLCAdjuvant Trials in Early Stage NSCLC

StageStage No. No. Intervention InterventionCALGB 9633CALGB 9633 IBIB 500 Carboplatin/Paclitaxel 500 Carboplatin/PaclitaxelNCI-C*NCI-C* IB-II IB-II 480 480 Cisplatin/VinorelbineCisplatin/Vinorelbine


Recently Completed (+) Randomized Recently Completed (+) Randomized Adjuvant Trials in Early Stage NSCLCAdjuvant Trials in Early Stage NSCLC

StageStage No. No. Intervention InterventionCALGB 9633CALGB 9633 IBIB 500 Carboplatin/Paclitaxel 500 Carboplatin/PaclitaxelNCI-C*NCI-C* IB-II IB-II 480 480 Cisplatin/VinorelbineCisplatin/VinorelbineANITAANITA I-IIIA I-IIIA 840 840 Cisplatin/VinorelbineCisplatin/Vinorelbine


CALGB 9633 - 344 pts, stage IBCALGB 9633 - 344 pts, stage IB

• 4 cycles carboplatin/paclitaxel 4 cycles carboplatin/paclitaxel vs. observationvs. observation

• Radiation therapy not allowedRadiation therapy not allowed

• 2004 - HR 0.62; p = 0.0282004 - HR 0.62; p = 0.028

• 2006 - HR 0.80; p = 0.102006 - HR 0.80; p = 0.10

Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2009

Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2008

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9

Years

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9

Years

Pro

bab

ility

Pro

bab

ility

ObservationPaclitaxel + Carboplatin

ObservationPaclitaxel + Carboplatin

n=97

n=99

n=74n=74

HR = 0.66; 90% CI, 0.45-0.97; P=0.04 HR = 1.02; 90% CI, 0.67-1.55; P=0.51

Tumor ≥4 cm Tumor <4 cm

CALGB 9633 Overall Survival CALGB 9633 Overall Survival by Tumor Sizeby Tumor Size

RANDOMIZE

Vinorelbine 25 mg/m2 weekly x 16 plusCisplatin 50 mg/m2 day 1 & 8 q4wk

x 4 cycles

ELIGIBLE:

Resected IB and IIT2N0, T1N1, or

T2N1

No prior chemoNo RT

Observation

JBR.10

Winton T, et al. N Engl J Med. 2005;352:2589-2597.

Primary endpoint = overall survivalStratification:• Nodal status – N0 vs N1• RAS status

N = 240

N = 242

NCIC-CTG JBR.10NCIC-CTG JBR.10482 pts, stage IB-II482 pts, stage IB-II

• Stage IB-II onlyStage IB-II only• 4 cycles of post-op cis/vin vs. observation4 cycles of post-op cis/vin vs. observation• No radiation therapyNo radiation therapy• 15% survival advantage at 5 years15% survival advantage at 5 years

– 54% vs 69% alive (NEJM paper)54% vs 69% alive (NEJM paper)

• HR 0.69, p=.012 in 482 ptsHR 0.69, p=.012 in 482 pts• Benefit only in stage II in subset analysisBenefit only in stage II in subset analysis

– Although post-hoc analysis shows a benefit in Although post-hoc analysis shows a benefit in IB > 4cmIB > 4cm

Winton, Proc ASCO 2004 Abs:7018, 2004, NEJM 2005

Overall Survival by Treatment ArmOverall Survival by Treatment Arm

Absolute improvement in 5 yr OS = 11% (67% vs 56%); benefit persists at 9+ yrs Vincent, Butts et al, 2009, ASCO -7501

All Patients

Absolute improvement in 5 yr OS = 15% (69% vs 54%) Winton et al. NEJM 2005

HR 0.69

5 yr: 69% vs 54%

MST 94 m vs 73 m

Fig.1

5 yr: 67% vs 56%

MST 94m vs 72m

At RiskObservationVinorelbine

Stratified Log-Rank: p=0.04HR: 0.780(0.613, 0.993)

'

Observation Vinorelbine

Perc

enta

ge0

20

40

60

80

100

0

240242

3

155182

6

117135

9Time(Years)

5867

12

912

15

00

Cumulative Incidence Plots for Disease Cumulative Incidence Plots for Disease and Non-disease Related Deathsand Non-disease Related Deaths

0 2 4 6 8 10 12 14

0.0

0.2

0.4

0.6

0.8

1.0

Time(Years)

Cum

ulat

ive

Pro

babi

lity

Observation/Disease Related

Chemotherapy/Disease Related

Observation/Non-Disease Related

Chemotherapy/Non-Disease Related

Test for Disease Related Deaths

========================

Log-Rank Test p-value = 0.027

Fine-Gray Test p-value = 0.023

--------------------------------------------

Test for Non-Disease Related Deaths

=============================

Log-Rank Test p-value = 0.660

Fine-Gray Test p-value = 0.622

-----------------------------------------------------

Stage IB AnalysisStage IB Analysis

T < 4 cm T ≥ 4 cm

HR OS p HR OS p

CALGB 9633 1.02 .51 0.66 .04

JBR.10 1.73 .07 0.66 .13

No Chemo Benefit

Potential Chemo Benefit

Strauss JCO 2008

ANITA - 840 pts, stage IB-IIIAANITA - 840 pts, stage IB-IIIA

• 1:1 Randomization post-resection1:1 Randomization post-resection– Vinorelbine (30 mg/m2) Q wk X 16 +Vinorelbine (30 mg/m2) Q wk X 16 + Cisplatin 100 mg/m2 Q 4 wks X 4 vsCisplatin 100 mg/m2 Q 4 wks X 4 vs– ObservationObservation

• Radiation therapy allowedRadiation therapy allowed• 8.6% survival advantage at 5 years (persists at 7 8.6% survival advantage at 5 years (persists at 7

yr)yr) – 42.6% vs 51.2% alive42.6% vs 51.2% alive

• HR 0.7 [0.66-0.95], p =.013HR 0.7 [0.66-0.95], p =.013• Benefit only in stage II and IIIABenefit only in stage II and IIIA

Douillard Lancet Oncol. 7:719, 2006

ANITA: Rand Phase III Trial of Vinorelbine and ANITA: Rand Phase III Trial of Vinorelbine and Cisplatin vs Obs in Resected stage I-III NSCLC:Cisplatin vs Obs in Resected stage I-III NSCLC:

DemographicsDemographics

• 840 pts accrued from 12/94 through 12/00840 pts accrued from 12/94 through 12/00• Median F/U > 70 mosMedian F/U > 70 mos• Each arm well balanced Each arm well balanced • Median age 59 (18 – 75)Median age 59 (18 – 75)• 86% male86% male• 95% PS 0-195% PS 0-1• 59% Squamous ca59% Squamous ca• 37% pneumonectomy37% pneumonectomy• StageStage

– I – 35%I – 35%– II – 30%II – 30%– III – 35%III – 35%


Overall survival - ITT populationOverall survival - ITT population

months

Su

rviv

al D

istr

ibu

tion

Fu

nct

ion

1.00

0.75

0.50

0.25

00 20 40 60 80 100 120

OBS. NVB + CDDP

Median months 43.8 65.8

P-value 0.013

Hazard Ratio 0.79 [0.66 - 0.95]

ObsObs

NVB + CDDPNVB + CDDP

Abstract #7013: ANITA Trial


ANITA: Randomized Phase III Trial of ANITA: Randomized Phase III Trial of Vinorelbine and Cisplatin vs Observation Vinorelbine and Cisplatin vs Observation

in resected stage I-III NSCLCin resected stage I-III NSCLCArm Observation Adjuvant

No 433 407

RFS (mo) 21 36

Median Surv (mo)* 44 66

2 yr OS 63 68

5 yr OS 43 51

7 yr OS 37 48

5 yr OS

Stage I 62 63

Stage II 39 52

Stage III 26 42

* P =0.002, HR 0.76 Douillard Lancet Oncol. 7:719, 2006

ANITA: Randomized Phase III Trial of Vinorelbine ANITA: Randomized Phase III Trial of Vinorelbine and Cisplatin vs Obs in resected stage I-III NSCLC and Cisplatin vs Obs in resected stage I-III NSCLC

Adjuvant ToxicitiesAdjuvant Toxicities

Douillard et al ASCO 2005, A-7013, p624

Neutropenia Gr 3+4 86%

Febrile Neutropenia 12.5%

Nausea-Vomiting Gr 3+4 27%

Aesthenia 28%

Constipation 5%

Peripheral Neuropathy 3%

Drug-Related Fatality 1%

LACE:Trials and patientsLACE:Trials and patients

• 5 trials including 5 trials including 4,584 patients4,584 patients• Median Median follow-up: 5.1 yearsfollow-up: 5.1 years (3.1 – 5.9) (3.1 – 5.9)• 80% male 80% male • Median age 59 years, Median age 59 years, 9% 9% >> 70 years old 70 years old • Pathological Stage: Pathological Stage: IA: 8%,IA: 8%, IB: 30%, II: 35%, III: 27%IB: 30%, II: 35%, III: 27%• Surgery: 31% pneumonectomySurgery: 31% pneumonectomy• Histology: Histology: 49% squamous cell, 49% squamous cell, 39% adenocarcinoma, 12% other39% adenocarcinoma, 12% other

Pignon Proc ASCO 2006 abs 7008

Survival curveSurvival curveChemotherapyNo chemotherapy

Su

rviv

al (%

)

0

20

40

60

80

100

Time from randomization (Years)0 1 2 3 4 5 > 6

61.0

48.857.1

43.5

Absolute difference

at 3 years: at 5 years:

3.9% + 1.5% 5.3% + 1.6%

ChemotherapyNo chemotherapy

Su

rviv

al (%

)

0

20

40

60

80

100

Time from randomization (Years)0 1 2 3 4 5 > 6

61.0

48.857.1

43.5

Absolute difference

at 3 years: at 5 years:

3.9% + 1.5% 5.3% + 1.6%

CT effect & stageCT effect & stage

CT may be detrimental for CT may be detrimental for stage IAstage IA, but stage IA , but stage IA patients were generally not given the potentially patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of best combination cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages)stage IA patients versus ~43% for other stages)

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage-Specific Hazard RatiosStage-Specific Hazard RatiosRecent Adjuvant TrialsRecent Adjuvant Trials

TrialTrial I < 4 cmI < 4 cm I I >> 4 cm 4 cm IIII IIIAIIIA

IALTIALT 0.95 0.93 0.79

BR-10BR-10 1.73 0.66 0.59 N/A

ANITAANITA 1.10 0.71 0.69

CALGBCALGB 1.02 0.66 N/A N/A

LACELACE 1.41* 0.91* 0.83 0.83

NegativeNegative PositivePositive

IndeterminateIndeterminate Not studiedNot studied* 3 cm as cut point

Therapeutic ImplicationsTherapeutic Implications• Short course adjuvant, platinum-based Short course adjuvant, platinum-based

therapy has emerged as standard practice therapy has emerged as standard practice in resected stage Ib-IIIa NSCLCin resected stage Ib-IIIa NSCLC

• Ongoing controversies re:Ongoing controversies re:– Molecular SelectionMolecular Selection– Influence of Age on OutcomeInfluence of Age on Outcome– Ideal platinating agent: carbo vs cisplatinIdeal platinating agent: carbo vs cisplatin– Choice of partner agentChoice of partner agent– Impact of StageImpact of Stage– Role of targeted agentsRole of targeted agents– Utility of RT in IIIA (N2)Utility of RT in IIIA (N2)

Potential Benefit Potential Benefit from Adjuvant Systemic Therapyfrom Adjuvant Systemic Therapy

Potential Benefit Potential Benefit from Adjuvant Systemic Therapyfrom Adjuvant Systemic Therapy

100

80

60

40

20

0Dis

ease F

ree P

ati

en

ts (

%)

1086420

Years

Patients cured with local regional therapy

Patients with residual micrometastases resistant to adjuvant therapy

Patients with residual micrometastasessensitive to adjuvant therapy

Prognostic Markers ?

Predictive Markers ?

Influence of Age on OutcomeInfluence of Age on Outcome

Elderly Specific Analyses: BR10Elderly Specific Analyses: BR10Pepe et al ASCO ’06, A-7009Pepe et al ASCO ’06, A-7009

• 65: designated cut-off65: designated cut-off– 327 younger pts (68 %)327 younger pts (68 %)

– 155 older pts (32 %)155 older pts (32 %)

• Baseline demographics similar except Baseline demographics similar except for histology and PSfor histology and PS

Cohort Younger Older P value

Adenoca 58% 43% 0.001

Squamous 32% 59% 0.001

PS 0 53% 42% 0.01

JBR-10 Outcomes by AgeJBR-10 Outcomes by Age• Worse PS in olderWorse PS in older;; fewer PS 0 fewer PS 0 >65 >65 (53% vs 41%, = 0.01)(53% vs 41%, = 0.01)• adeno>squam in younger, squam>adeno in older pts.adeno>squam in younger, squam>adeno in older pts.• Patients >65 received significantly less chemoPatients >65 received significantly less chemo

– no significant diffno significant diff.. in toxicity, or growth factor support in toxicity, or growth factor support– mmore elderly patients refused treatmentore elderly patients refused treatment

• OS 46% vs. 66% for obs. vs. chemo in pts >65OS 46% vs. 66% for obs. vs. chemo in pts >65– Overall Survival HR 0.61 [0.38-0.98], p =.04 in elderlyOverall Survival HR 0.61 [0.38-0.98], p =.04 in elderly

• OS 58% vs. 70% for obs. vs. chemo in pts OS 58% vs. 70% for obs. vs. chemo in pts <<6565– Overall Survival HR 0.77 [0.54-10.9], p = 0.14 in youngOverall Survival HR 0.77 [0.54-10.9], p = 0.14 in young

• Older patients (>75) Older patients (>75) – Worse survivalWorse survival regardless of Rx regardless of Rx, but same when corrected for , but same when corrected for

disease-specific survivaldisease-specific survival– Benefit from chemo not seen in pts >75 (?harmful)Benefit from chemo not seen in pts >75 (?harmful)– However, patient numbers are too small to answer clearlyHowever, patient numbers are too small to answer clearly

Pepe C, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol. 2007 Apr 20;25(12):1553-61

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17442999&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

BR10: Overall Survival BR10: Overall Survival by by Age GroupAge Group

0 2 4 6 8 10 12

0.0

0.2

0.4

0.6

0.8

1.0

Time (Years)

Pro

bab

ility >75 N = 23

71-75 N = 48

66-70 N = 84

0-65 N = 327

0 2 4 6 8 10 12

0.0

0.2

0.4

0.6

0.8

1.0

>75 N = 23

75 N = 459

Log-Rank, p =0.0006

H-R =2.38

26%

63%

Pepe C, et al Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol. 2007 Apr 20;25(12):1553-61

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17442999&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Ideal Platinating AgentIdeal Platinating Agent

Argument Favoring CarboplatinArgument Favoring Carboplatin

• The best results obtained in stage IB have The best results obtained in stage IB have been observed with CbPac (not with DDP-been observed with CbPac (not with DDP-based regimens)based regimens)– Subset analysis in > 4 cm tumors demonstrates a Subset analysis in > 4 cm tumors demonstrates a

survival benefitsurvival benefit• CbPac has not been tested in stage II/IIIA in CbPac has not been tested in stage II/IIIA in

the adjuvant settingthe adjuvant setting– Absence of data does not prove absence of benefit Absence of data does not prove absence of benefit

(….absence of proof is not proof of absence….)(….absence of proof is not proof of absence….)• Finally, a substantial percentage of adj pts are Finally, a substantial percentage of adj pts are

poor candidates for cisplatin-based therapy poor candidates for cisplatin-based therapy due to age, co-morbidities, etcdue to age, co-morbidities, etc

Which Agents Partner Best Which Agents Partner Best with Platinumwith Platinum

M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N.

Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T.

Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas

on behalf of the TREAT investigatorson behalf of the TREAT investigators

LACE-Metaanalysis NCIC-JBR .10

No treatment 9% 4.5%

Treatment incomplete 24 %(≤ 2 cycles)

50%(< 4 cycles)

• early death or progression 9% 5%

• toxicity 34% 13%

• patient refusal 35% 29%

Therapy delay 55%

Dose reductions 77%

Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009

TREAT Rationale:TREAT Rationale:

• Adjuvant CTX: mainly Cisplatin / Vinorelbine

• Need: reduction of toxicity, improvement of dose delivery & compliance

• Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low

toxicities

Rationale: Dose delivery: Adjuvant CTX

TREAT: Design

Cisplatin / Vinorelbine (CVrb)

Cisplatin / Pemetrexed (CPx)

50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4

75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4

R0Winton et al., N Engl J Med (2005) 352: 258

InclusionInclusion • NSCLC stages IB, IIA, IIB, T3N1M0

• ≤ 42 Tage postoperatively, R0, systematic LN-dissection

• ECOG 0, 1

• amenable to Cisplatin treatment

StratificationStratification • Center

• Nodal status (N0 versus N1)

• Surgical procedure (lobectomy vs pneumonectomy)

Study conductStudy conduct• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132

patients)• Treatment until 2/2010, primary endpoint analysis 12/2010

Primary endpointPrimary endpoint

Clinical FeasibilityClinical Feasibility• No death due to cancer, toxicity, comorbidity• No Non-acceptance by patients leading to premature withdrawal• No observation of DLT

Neutropenia grade 4 > 7 dNeutropenia grade 3/4 with fever/infectionThrombocytopenia grade 4 > 7 dThrombocytopenia any grade with bleedingNon-hematologic toxicity grade 3/4 related to CTX

Secondary endpointsSecondary endpoints

Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse

TREAT: Conduct / endpoints

Kreuter et al., BMC Cancer, 2007

Study conductStudy conduct• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132

patients)• Treatment until 2/2010, primary endpoint analysis 12/2010

Primary endpointPrimary endpoint

Clinical FeasibilityClinical Feasibility [considered promising if > 80%]• No death due to cancer, toxicity, comorbidity• No Non-acceptance by patients leading to premature withdrawal• No observation of DLT

Neutropenia grade 4 > 7 dNeutropenia grade 3/4 with fever/infectionThrombocytopenia grade 4 > 7 dThrombocytopenia any grade with bleedingNon-hematologic toxicity grade 3/4 related to CTX

Secondary endpointsSecondary endpoints

Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse

TREAT: Conduct / endpoints

Kreuter et al., BMC Cancer, 2007

CharacteristicsCharacteristics CPxCPx(n=67)(n=67)

CVbCVb(n=65)(n=65)

TotalTotal(n=132)(n=132)

Age (years [range]) 58 [40-73] 60 [38-74] 59 [38-74]

Gender (%)• male • female

7228

77 23

7426

Smoking status (%)• Smoker • Ex-smoker• Non-smoker • Not available

336160

2671

1.5 1.5

29664 1

Stage (%)Stage (%)

IB 37 38 38

IIA 12 8 10

IIB 46 48 47

T3N1 5 6 5

TREAT: Characteristics

CharacteristicsCharacteristics CPxCPx(n=67)(n=67)

CVbCVb(n=65)(n=65)

TotalTotal(n=132)(n=132)

Surgical procedures (%)Surgical procedures (%)

Lobectomy 84 82 83

Pneumonectomy 12 15 14

Complex resections 4 3 3

Histology (%)Histology (%)

Squamous cell carcinoma 45 42 43

Non-squamous 55 58 57

• Adenocarcinoma 37 44 41

• Large cell carcinoma 9 9 9

• Mixed cell carcinoma 9 5 7

TREAT : Characteristics

CPxCPx CVbCVb

Feasibility rate (%) Feasibility rate (%) 95.5 95.5

(CI 87.5-99.1)(CI 87.5-99.1)

75.4 75.4

(CI 63.1-85.2)(CI 63.1-85.2)

Death (%) 1.5 3.1

Withdrawal of consent (%) 0 6.2

DLT (%) 3.0 15.4

Reasons for DLT (events) Reasons for DLT (events) ** patients (n=2)patients (n=2) patients (n=10)patients (n=10)

G4 neutropenia >7d 0 4

G4 thrombocytopenia >7d 0 0

G3/4 febrile neutropenia 1 5

Thrombocytopenia with bleeding 0 0

G3/4 non-hematologic toxicity 2 1

Results: Primary endpoint - feasibility

* multiple reasons possible

p = 0.0010p = 0.0010

EOTEOT CPxCPx CVbCVb

Regular EOT (%) 77.6 36.9

Earlier termination of therapy (%) 22.4 63.1

Reasons for earlier termination (events)*Reasons for earlier termination (events)* patients (n=15)patients (n=15) patients (n=41)patients (n=41)• Unacceptable toxicity according to protocol** 4 19

• Unacceptable toxicity perceived by patient 6 7

• Relapse of disease 0 2

• Withdrawal of consent 0 4

• Death (therapy related) 1 (0) 2 (0)

• Non-compliance to protocol 0 2

• Medical decision by investigator 4 5

• Major protocol violation 0 1

• Other reasons 0 4

Results: End of therapy

*multiple reasons possible**delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

ToxicityToxicity CPxCPx CVbCVb

Mean Number(AE / SAE)

6.8 / 0.3 6.9 / 0.2

HematologicToxicity G3/4 (%)

10.5 76.5

Non-hematologic Toxicity G3/4 (%) 33 31

Hematologic Toxicity (%) G3/4 G3/4

Anemia 0 1.5

Thrombocytopenia 0 0

Neutropenia 9 69

Febrile Neutropenia 1.5 6

TREAT: Toxicity

p<0.0001

p=0.7988

TREAT: Time to treatment failureTREAT: Time to treatment failure

TtTF:TtTF:

Time from surgery Time from surgery to withdrawal due to withdrawal due

to to

• AEAE• progression / progression /

relapse / deathrelapse / death• failure to returnfailure to return

to therapyto therapy• refusal of refusal of

treatment / treatment / withdrawal of withdrawal of consent consent

p<0.001W

ithdra

wal pro

babili

ty

• CPx safe and feasible CPx safe and feasible less toxicity compared to CVbless toxicity compared to CVb

superior dose delivery compared to CVbsuperior dose delivery compared to CVb

high dose density (mg/mhigh dose density (mg/m22/week)/week)

• Dose delivery failure in CVb Dose delivery failure in CVb

mostly due to Vb (delivery d15, d22)mostly due to Vb (delivery d15, d22)

• Efficacy: longer follow up to be awaitedEfficacy: longer follow up to be awaited

TREAT: Conclusions

Molecular SelectionMolecular Selection

Immunohistochemical (IHC) Immunohistochemical (IHC) Staining of the Staining of the Excision Repair Cross-Complementing 1 Excision Repair Cross-Complementing 1 (ERCC1) (ERCC1) PProtein as rotein as PPredictor redictor of Benefitof Benefit from from adjuvant chemotherapy (CT) in the adjuvant chemotherapy (CT) in the

International Lung Cancer Trial (IALT)International Lung Cancer Trial (IALT)

761 pts. (28 centers,14 countries) evaluable for ERCC1 expression ERCC1 repairs cisplatin-DNA adducts, so expression indicates platinum resistance ERCC1 a “double-edged sword”; worse prognosis of NSCLC if low expression, but more responsive to platinum

Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:983-991

ERCC1-Negative: ERCC1-Negative: Overall SurvivalOverall Survival

4781121161194224355991120163202

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5YearsNo at riskChemotherapy

Control

Control

Chemotherapy

Overa

ll Surv

ival

Adjusted HR = 0.6595% PI [0.50-0.86], p = 0.002

346285121147165336996127149170

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5YearsNo at risk

ChemotherapyControl

Overa

ll Surv

ival

Control

Chemotherapy

Adjusted HR = 1.14, 95% CI [0.84-1.55], p = 0.40

ERCC1-Positive: Overall Survival

47%

39%

46%

40%

Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:983-991

IFCT-0801 IFCT-0801 TASTETASTE

TATAilored post-ilored post-SSurgical urgical TTherapy in herapy in EEarly stage NSCLCarly stage NSCLC

Principal InvestigatorJean-Charles SORIAInstitut Gustave Roussy - Villejuif

Biological CoordinatorMarie WislezHôpital Tenon - Paris

Erlotinib

CDDP-Pemetrexed

Observation

ERCC1-

ERCC1+

EGFR wt

Experimental ArmCustomized

Control ArmCDDP - pemetrexed

EGFRmutated

TASTE designTASTE design

Non-SCC NSCLC stage II and IIIA (non-N2)

TASTE ResultsTASTE Results• 150 pts randomized between May 2009 and July 2012, 150 pts randomized between May 2009 and July 2012, • 74 in arm A (PEM/DDP) and 76 in arm B (Selected)74 in arm A (PEM/DDP) and 76 in arm B (Selected)• Most pts were male (61%), > 60 years (51%), and smokers (91%)Most pts were male (61%), > 60 years (51%), and smokers (91%)• Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. • ERCC1 was positive in 38 pts (19 in each arm) – only 25%, not 44% expectedERCC1 was positive in 38 pts (19 in each arm) – only 25%, not 44% expected• EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B). EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B).

– Arm A, all pts received CP. Arm A, all pts received CP. – Arm B, Arm B,

• 7 pts received erlotinib, 7 pts received erlotinib, • 53 pts received CP 53 pts received CP • 16 were observed16 were observed

• Median exposure time to erlotinib was 276 days (10-365).Median exposure time to erlotinib was 276 days (10-365).• Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no

febrile neutropenia). febrile neutropenia). • Success rate was 80% (120 out of 150 pts): appropriate Tx assignment and TxSuccess rate was 80% (120 out of 150 pts): appropriate Tx assignment and Tx

68

Soria J-C et al A-7505, ASCO ‘13

TASTE ConclusionsTASTE Conclusions• Met its primary end point for the phase II component, demonstrating Met its primary end point for the phase II component, demonstrating

feasibility of a national biology-driven trial in the adjuvant setting. feasibility of a national biology-driven trial in the adjuvant setting. • Nevertheless, the phase III was canceled due to the unexpected unreliability Nevertheless, the phase III was canceled due to the unexpected unreliability

of the ERCC1 IHC read-out. of the ERCC1 IHC read-out. – Current commercial antibodies are unable to distinguish all Current commercial antibodies are unable to distinguish all

isoforms of ERCC1isoforms of ERCC1

• TASTE Needs to be redone with accurate ERCC1 IHC AbTASTE Needs to be redone with accurate ERCC1 IHC Ab• May have been responsible for the (-) MadeIT phase III trial in advanced May have been responsible for the (-) MadeIT phase III trial in advanced

NSCLC (relied on PCR mRNA probes and AQUA)NSCLC (relied on PCR mRNA probes and AQUA)

69

TASTE Implications

Soria J-C et al A-7505, ASCO ‘13

Role of Targeted TherapyRole of Targeted Therapy

ECOG 1505: Adjuvant BevacizumabECOG 1505: Adjuvant Bevacizumab

RRAANNDDOOM M I IZZEE

STRATIFIED:STRATIFIED:

StageStageHistologyHistologyGenderGenderChemo Chemo regimen*regimen*

ChemotherapyChemotherapyX 4 cyclesX 4 cycles

ELIGIBLE:ELIGIBLE:

Resected IB^-IIIAResected IB^-IIIA

LobectomyLobectomyNo prior chemoNo prior chemoNo planned XRTNo planned XRTNo h/o CVA/TIANo h/o CVA/TIANo ATE w/in 1 yrNo ATE w/in 1 yr

ChemotherapyChemotherapyx 4 cyclesx 4 cyclesPlusPlusBevacizumabBevacizumabX 1 yearX 1 year

*Investigator Choice of 4 chemo regimens*Investigator Choice of 4 chemo regimens^ Revised to exclude IB < 4cm^ Revised to exclude IB < 4cmN >1500; closed to accrual summer 2013N >1500; closed to accrual summer 2013

ECOG 4599: Overall SurvivalECOG 4599: Overall Survival

0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n Su

rviv

ing

0 6 42 4818 3012 24 36

Months

HR=0.80; P=0.013BV/PC 12.3 moPC 10.3 mo

Median Survival

1-year survival51% vs 44%

2-year survival23% vs 15%

Sandler, et al. NEJM. 355;24. Dec 14 2006.

Chemotherapy RegimensChemotherapy Regimens

• Therapy to start 6-12 weeks post-operativelyTherapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12 wks)Investigator Choice of Chemo - 4 cycles (12 wks)

• Cisplatin/VinorelbineCisplatin/Vinorelbine– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 dCis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d

• Cisplatin/DocetaxelCisplatin/Docetaxel– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 dCis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d

• Cisplatin/GemcitabineCisplatin/Gemcitabine– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 dCis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d

• +/- Bevacizumab 15 mg/kg q 21 days x 12 mos +/- Bevacizumab 15 mg/kg q 21 days x 12 mos

Chemotherapy Regimens: Chemotherapy Regimens: amended 2010amended 2010

• Therapy to start 6-12 weeks post-operativelyTherapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12 wks)Investigator Choice of Chemo - 4 cycles (12 wks)

• Cisplatin/PemetrexedCisplatin/Pemetrexed– Cis 75 mg/m2 d1, Pemetrexed 500 mg/m2 d1Cis 75 mg/m2 d1, Pemetrexed 500 mg/m2 d1

• Cisplatin/VinorelbineCisplatin/Vinorelbine– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 dCis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d

• Cisplatin/DocetaxelCisplatin/Docetaxel– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 dCis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d

• Cisplatin/GemcitabineCisplatin/Gemcitabine– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 dCis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d

• +/- Bevacizumab 15 mg/kg q 21 days x 12 mos +/- Bevacizumab 15 mg/kg q 21 days x 12 mos

RADIANT Trial: RADIANT Trial: Adjuvant Trial of Erlotinib in NSCLCAdjuvant Trial of Erlotinib in NSCLC

Stage IB, II, or IIIA NSCLC*

Complete surgical resection

And subsequent adjuvant chemo

No prior or concurrent neoadjuvant or adjuvant

N=1654

Arm AErlotinib qd 2

years

Arm BPlacebo qd 2 years

RANDOMIZE٭

*Enriched Population: FISH and/or IHC (+)

2

1

RADIANT Trial: RADIANT Trial: Adjuvant Trial of Erlotinib in NSCLCAdjuvant Trial of Erlotinib in NSCLC

Stage IB, II, or IIIA NSCLC*

Complete surgical resection

And subsequent adjuvant chemo

No prior or concurrent neoadjuvant or adjuvant

N=1654

Arm AErlotinib qd 2

years


RANDOMIZE٭

*Enriched Population: FISH and/or IHC (+)

2

1

Accrual Completed

April, 2010

IPASS: Progression-free survival in EGFR IPASS: Progression-free survival in EGFR mutation positive and negative patientsmutation positive and negative patients

Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p<0.0001

HR (95% CI) = 0.48 (0.36, 0.64)

p<0.0001No. events gefitinib, 97

(73.5%)No. events C/P, 111 (86.0%)Median PFS G, 9.5 months

Median PFS C/P, 6.3 months

HR (95% CI) = 2.85 (2.05, 3.98)

p<0.0001No. events gefitinib , 88

(96.7%)No. events C/P, 70 (82.4%)Median PFS G, 1.5 months

Median PFS C/P, 5.5 months

132 71 31 11 3 0129 37 7 2 1 0

108103

0 4 8 12 16 20 24

GefitinibC/P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y of

pro

gre

ssio

n-

free s

urv

ival

Patients at risk :91 4 2 1 0 085 14 1 0 0 0

2158

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y of

pro

gre

ssio

n-

free s

urv

ival

Gefitinib (n=91)Carboplatin/paclitaxel (n=85)

Months Months

Gefitinib (n=132)Carboplatin/paclitaxel (n=129)

Fukuoka et al, abstract 8006, ASCO 2009; Mok et al NEJM 2010

Phase II trial SELECT trial: adjuvant erlotinib in resected, Phase II trial SELECT trial: adjuvant erlotinib in resected, early stage NSCLC pts with early stage NSCLC pts with EGFR EGFR mutationsmutations

PI L Sequist PI L Sequist

Resected stage IA-IIIA NSCLC

Screen tumor for activating EGFR mutations (del 19, L858R)

Adjuvant erlotinib x 2 years

+/- adjuvant chemo

Enroll if: screen + or documented EGFR mutation positive –and-No evidence recurrence on baseline CT scans

Surveillance CT scans and CTC analysis q 6 mos x 3 years then q 12 mos x 2 years

Biopsy at recurrence, sequence EGFR gene for new mutations, FISH for EGFR and MET copy number

surveillance

SCREENING PHASE TREATMENT PHASE

N=100Primary Endpoint: Two year disease-free survival

SELECT Trial: Adjuvant Erlotinib in Resected SELECT Trial: Adjuvant Erlotinib in Resected NSCLCNSCLC

Disease Free SurvivalDisease Free Survival

BR 19: Adjuvant Trial of BR 19: Adjuvant Trial of Gefitinib in NSCLCGefitinib in NSCLC

Stage IB, II, or IIIA NSCLCComplete surgical resectionNo prior or concurrent neoadjuvant or adjuvant N=1242

Modified 2004 to allow adjuvant chemotherapy ٭

Arm AGefitinib qd 2 years


CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol. Clinical Trials (PDQ®). At: www.cancer.gov. Commenced October 2002.

RANDOMIZE٭

Goss ASCO 2010 Abstr LBA7005

* Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.51]

ALCHEMIST

E4512 A081105 A151216

Target ALK+ EGFRmut Registry

Prevalence ~5% ~10% All comers

n 336 410 6000-8000

Primary Endpt DFS-OS OS --

Power 80% 85% --

One-sided α 0.025 0.05 --

HR 0.67 0.67 --

Adjunct

Peripheral screening for

ALK; RTPCR to identify fusion

partners

Targeted sequence and

kinome analysis; PRO

and QOL

Extended sequencing for

additional targets; correlation with

local testing

VaccinesVaccines

MAGE-A3 AntigenMAGE-A3 Antigen(melanoma antigen family A, 3)(melanoma antigen family A, 3)

• Truly tumor-specificTruly tumor-specific–Not expressed on normal cells Not expressed on normal cells (RT-PCR)(RT-PCR)–Expressed by various tumor typesExpressed by various tumor types

• Lung Lung 35-50%35-50%• BladderBladder 35%35%• Head & Neck Head & Neck 49%49%• MelanomaMelanoma 74%74%

• Associated withAssociated with poorer prognosispoorer prognosis(Bolli et al.,2002; Gure et al.,2005)(Bolli et al.,2002; Gure et al.,2005)

• Member of a largeMember of a large family of genesfamily of genes (portfolio)(portfolio)

MAGE A3 ASCI* randomized phase IIMAGE A3 ASCI* randomized phase II

• Stage pIB or pII: double-blind, randomly assigned 2:1 Stage pIB or pII: double-blind, randomly assigned 2:1 to postoperative MAGE-A3 vaccination or placeboto postoperative MAGE-A3 vaccination or placebo . .

• Vaccination was started Vaccination was started >>6 weeks after surgery, with 5 6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 monthsvaccinations every 3 months. .

• Other anti-cancer adjuvant therapy was not allowed. Other anti-cancer adjuvant therapy was not allowed. • Primary endpoint was time-to-recurrence, other Primary endpoint was time-to-recurrence, other

endpoints were recurrence rates at different times, endpoints were recurrence rates at different times, and survival. and survival.

* antigen-specific cancer immune therapeuticVansteenkiste et al, ASCO 2006, abstract 7019

Safety StatusSafety Status

• 182 patients / 1214 MAGE-A3182 patients / 1214 MAGE-A3 doses doses administeredadministered

• Well toleratedWell tolerated• Mild grade 1 or 2 toxicitiesMild grade 1 or 2 toxicities• Local or systemic reactions, Local or systemic reactions, 48 hours 48 hours

• 29 grade 3 or 4 adverse events in 21 29 grade 3 or 4 adverse events in 21 patientspatients

• Three grade 3 events, possibly related to Three grade 3 events, possibly related to treatmenttreatment

• Leading to Leading to withdrawal of 2 patientswithdrawal of 2 patients – (local pain, COPD exacerbation)(local pain, COPD exacerbation)

HR=0.73 (95% CI = 0.44 - 1.2)p=0.107 10% one-sided

Disease-Free IntervalDisease-Free Interval

Vansteenkiste et al, ASCO 2006, abstract 7019

Disease-Free Interval

Final analysis 05 Oct, 2006Cox regression model (95% confidence interval)

P-value from Cox regr. model adjusted for stratification covariates

HR with a 10% one-sided

0.00 0.50 1.00 1.50 2.00 Hazard ratio

« Control » better« MAGE-A3 » better

0.73

0.66

HR = 0.73 (0.44-1.20)

HR = 0.73 (0.45-1.16)

HR = 0.66 (0.36-1.20)

0.73Disease-Free Survival

Overall Survival

Efficacy Endpoints Overview

P=0.107

Resectable NSCLC

Surgery

Pathological stage IB, II, IIIA

R

MAGE-A3 +AS15 Placebo

No chemotherapy Chemotherapy(up to 4 cyclesplatinum based chemotherapy)

R

MAGE-A3 +AS15

Placebo

MAGE Trial DesignMAGE Trial Design

MAGRIT Trial

MAGRIT: Phase IIIMAGRIT: Phase III

• Largest lung cancer study EVERLargest lung cancer study EVER

• Began in October 2007Began in October 2007

• Goal: 2270 patients from 400 centers Goal: 2270 patients from 400 centers in 33 countries in Europe, North and in 33 countries in Europe, North and South America, Asia, AustraliaSouth America, Asia, Australia

• 2289 ultimately enrolled2289 ultimately enrolled

Role of Adjuvant RT in Stage II Role of Adjuvant RT in Stage II and Stage IIIAand Stage IIIA

Should the pt receive adj RT?Should the pt receive adj RT?

1)1) YesYes

2)2) NoNo

3)3) MaybeMaybe

Adjuvant Radiotherapy:Adjuvant Radiotherapy:Meta-analysis 1998Meta-analysis 1998

• Individual data from 9 randomized trials Individual data from 9 randomized trials including 2128 patientsincluding 2128 patients

• Treatment details (staging, surgery, RT) Treatment details (staging, surgery, RT) highly variable among serieshighly variable among series

• PORT: better local control: 29% fewer local PORT: better local control: 29% fewer local recurrences - 195 LR vs 276 LR for no RTrecurrences - 195 LR vs 276 LR for no RT

• Overall HR = 1.21 (1.08-1.34) ~ survival Overall HR = 1.21 (1.08-1.34) ~ survival decrement of 7 % at two years (55% vs 48%)decrement of 7 % at two years (55% vs 48%)

• Increase risk greater for early stage Increase risk greater for early stage patients(Stage I/II vs. III)patients(Stage I/II vs. III)

Lancet 25 July 1998Lancet 25 July 1998

PORT Meta-analysisPORT Meta-analysisSurvival CurvesSurvival Curves

Stewart et al Lancet 1998Stewart et al Lancet 1998

PORT - Heterogeneity of HazardPORT - Heterogeneity of Hazard

• No increased risk No increased risk for patients with N2 for patients with N2 diseasedisease

• Patients with the Patients with the least to gain have least to gain have the most to losethe most to lose


PORT Meta-analysisPORT Meta-analysisMethodologic FlawsMethodologic Flaws

• Variable and unspecified stagingVariable and unspecified staging• Variable and unspecified interval between resection and Variable and unspecified interval between resection and

PORTPORT• Inadequate RTInadequate RT

– Suboptimal doses; large fieldsSuboptimal doses; large fields– Poor treatment planningPoor treatment planning– Outmoded techniques (e.g.: use of low-energy photons or Outmoded techniques (e.g.: use of low-energy photons or 6060Co Co

for a substantial proportion of patients)for a substantial proportion of patients)

• Inclusion of NInclusion of N00 patients patients

• Unpublished data (2 of 9 studies)Unpublished data (2 of 9 studies)• Relatively short F/U (< 4 yrs)Relatively short F/U (< 4 yrs)


Risks of PORT with Modern Risks of PORT with Modern TechnologyTechnology

• Retrospective reviewRetrospective review– 202 patients treated with surgery and 202 patients treated with surgery and

PORT for Stage II and III diseasePORT for Stage II and III disease– Median dose 55 GyMedian dose 55 Gy– Actuarial rate of death from Actuarial rate of death from

intercurrent disease was 13.5% intercurrent disease was 13.5% compared to expected rate of 10%compared to expected rate of 10%

Machtay et al JCO 2001Machtay et al JCO 2001

CT RTCTRTOBS

0.00

0.25

0.50

0.75

1.00

DURATION OF SURVIVAL (MONTHS)

0 20 40 60 80 100 120

Su

rvi v

al

Dis

tri b

uti

on

Fu

nc

tio

n

IASLC 2005

ANITA TRIAL: N2 Disease – Influence of RT

CT RTCTRTOBS

0.00

0.25

0.50

0.75

1.00

DURATION OF SURVIVAL (MONTHS)

0 20 40 60 80 100 120

Su

rvi v

al

Dis

tri b

uti

on

Fu

nc

tio

n

IASLC 2005

ANITA TRIAL: N2 Disease – Influence of RT

RT Effect? Or Serendipity?

ANITA - PORT EvaluationANITA - PORT Evaluation• PORT: 33% on obs, 22% on chemoPORT: 33% on obs, 22% on chemo

• For all Chemo > XRT = chemo/XRT > 0For all Chemo > XRT = chemo/XRT > 0

• For N2 Chemo/XRT > chemo > XRT > 0For N2 Chemo/XRT > chemo > XRT > 0

XRT No No Yes Yes

Chemo No Yes No Yes

All pts MST 26mo 93mo 50mo 46mo

N2 MST 13mo 24mo 23mo 47mo

Rosell, IASLC 11, Abs Pr3, 2005

Lally, B. E. et al. J Clin Oncol; 24:2998-3006 2006

Plot of overall survival for N2 patients Plot of overall survival for N2 patients stratified by postoperative radiotherapy stratified by postoperative radiotherapy

(PORT) use – SEER data(PORT) use – SEER data

PORT ConclusionsPORT Conclusions

• PORT has no role in N0 or N1 diseasePORT has no role in N0 or N1 disease

• Role of PORT in N2 is controversialRole of PORT in N2 is controversial– Recent subset and retrospective analyses hint Recent subset and retrospective analyses hint

at benefitat benefit– Ongoing “Lung ART” trial in FranceOngoing “Lung ART” trial in France

• 700 pts with resected N2 randomized to PORT or not700 pts with resected N2 randomized to PORT or not• Adjuvant chemo allowed 1Adjuvant chemo allowed 1stst

• Accrual sluggishAccrual sluggish

““Lung ART”Lung ART”P.I. Dr Cécile Le PechouxP.I. Dr Cécile Le Pechoux

Completely resected N2 NSCLC Completely resected N2 NSCLC

SSUURRGGEERRYY

Conformal RTConformal RT

No post-op RTNo post-op RT

54 Gy/27-30 fxs54 Gy/27-30 fxs

Primary end-point: DFS (Sample size: 700 patients)Primary end-point: DFS (Sample size: 700 patients)

Pre or post-op chemotherapy allowedPre or post-op chemotherapy allowedConcomitant chemo not allowedConcomitant chemo not allowed

Sponsors: FNCLCC, IFCT, LARS-G, EORTCSponsors: FNCLCC, IFCT, LARS-G, EORTC

Conclusions: Adjuvant TherapyConclusions: Adjuvant Therapy

• Adjuvant Platinum-based Chemotherapy is the Adjuvant Platinum-based Chemotherapy is the Standard of Care for Resected Stage II-IIIA NSCLCStandard of Care for Resected Stage II-IIIA NSCLC– Improves OS 5%-15% at 5 years with newer drugsImproves OS 5%-15% at 5 years with newer drugs

• Fit elderly patients (< 75 yrs) benefit as much as Fit elderly patients (< 75 yrs) benefit as much as younger patientsyounger patients

• Ongoing trials with molecularly determined Tx, Ongoing trials with molecularly determined Tx, erlotinib, bevacizumab, vaccineserlotinib, bevacizumab, vaccines

• ControversiesControversies– Benefit in IBBenefit in IB– Neoadjuvant vs adjuvant therapy Neoadjuvant vs adjuvant therapy – Which chemotherapy to useWhich chemotherapy to use– PORTPORT

early stage nsclc: imprimatur of adjuvant therapy corey j langer md, facp professor of medicine...

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